HU203543B - Process for producing cyclohexane derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

A cyclohexane derivatlve of the formula: <CHEM> wherein R<1> is halomethyl; or arylthiomethyl which may have amino, lower alkoxy or acylamino, R<2> is lower alkoxy, <CHEM> R<4> is hydrogen, lower alkylcarbamoyl, lower alkylcarbamoyloxy(lower) alkylcarbamoyl, heterocyclic carbonyl or heterocyclic carbamoyl, or salt thereof. A process for preparing the cyclohexane derivative is also described, together with a pharmaceutical composition comprising the same as an active ingredient. The compounds exhibit angiogenesis inhibitory activity and are therefore useful in the treatment of, for example, tumours, rheumatoid arthritis, diabetic retinopathy and psoriasis.

Description

The present invention relates to a process for the preparation of novel cyclohexane derivatives. More particularly, the present invention relates to a process for the preparation of novel cyclohexane derivatives and their salts having an inhibitory effect on vascularization, and to a process for the preparation of pharmaceutical formulations containing the above active compounds.

The cyclohexane derivatives of the present invention are compounds of formula (I) wherein

R ¹ is a methyl group substituted by a halogen atom, or a phenylthiomethyl group optionally substituted on the phenyl group by an amino group, a C 1-4 alkoxy group or a C 1-4 alkanesulfonylamino group;

R ² is C 1-4 alkoxy;

R ³ is a group of formula (IV) or a group of formula (V), and

R ⁴ is hydrogen, C 1-4 alkylcarbamoyl, C 1-4 alkylcarbamoyloxy (C 1-5) alkylcarbamoyl, morpholinocarbonyl or morpholinocarbamoyl.

The process of the present invention provides compounds of formula (I) according to Methods 1 and 2 wherein R, R ³ and R ⁴ are as defined above;

X is halogen or phenylthio which may be monosubstituted by amino, C 1-4 -alkoxy or C 1-4 -alkanesulfonylamino;

R ⁵ is C 1 -C 4 alkanesulfonylamino.

The starting compounds of formula (Π) are obtained by standard procedures, for example, in the Journal of the American Chemical Society 94,2549. (1972) and exemplified in the Examples.

Interpretation of the above and other various terms used in the specification, example and figures is given below.

Suitable "C 1 -C 4 alkoxy" groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and the like.

Suitable salts of the compounds of formula (I) include inorganic or organic acid salts (e.g., hydrochloride, etc.).

The methods of the present invention are described in detail below

Procedure 1

The compounds of formula (I) or salts thereof may be prepared by reacting a compound of formula (Π) with a compound of formula (ΙΠ) or a salt thereof.

The salt of the compound of formula (ΙΠ) may be an inorganic or organic base salt (e.g., a pyridine salt, etc.).

The reaction is generally carried out in a solvent which does not adversely affect it. Examples of such solvents include methanol, ethanol, propanol, tetrahydrofuran, chloroform and the like.

The reaction temperature is not critical and may be carried out under cooling or heating

Procedure 2

Compounds of formula (Ic) may be prepared by reacting a compound of formula (Ib) or a salt thereof with an acylating agent.

The acylating agent useful in the reaction may be an organic acid, i.e., R ⁶ OH, wherein R ⁶ is C 1 -C 4 alkanesulfonyl or a reactive derivative thereof.

The reactive derivative of the compound of formula VI may be a conventional derivative such as an acid halide (e.g., acid chloride, acid bromide, etc.), acid azide, acid anhydride, activated acid amide, activated ester, isocyanate and the like.

When the free acid is used as the acylating agent, the acylation reaction is preferably carried out in the presence of a conventional condensing agent.

The reaction is preferably carried out in the presence of an inorganic or organic base.

The reaction is carried out in a solvent which does not adversely affect the reaction. Examples of such solvents include methanol, ethanol, propanol, tetrahydrofuran, chloroform, dichloromethane and the like.

The reaction temperature is not critical and may be carried out under heating or cooling.

The materials prepared in the above processes can be isolated, purified and converted to the desired salt form by conventional methods.

The compounds of formula (I) and their pharmaceutically acceptable salts are useful for inhibiting vascularization and are useful in the treatment of tumors, rheumatoid arthritis, diabetic retinopathy, psoriasis and the like.

The following test assay demonstrates the efficacy of the compounds of formula I in inhibiting vascularization.

Effect of compounds of formula I on endothelial cell growth

Human umbilical vein (HUVEC) endothelial cells were used in the experiment.

HUVEC (2 x 10 ³ cells per dose) cells were plated in 96-well microtiter plates pre-coated with human fibronectin and in MCDB 151 (GIBCO) medium supplemented with 15% FBS (fetal bovine serum), 100% micro g / ml. ECGS (endothelial cell growth additive) and 10 micro g / ml heparin were incubated for 5 days in the presence of the test compound at 37 ° C in 5% CO 2.

At the end of the experiment, HUVEC growth rate was measured by MTT (Cancer Treatment Reports, 71, 1141-1149 [1987]).

The compound tested inhibited the proliferation of human umbilical cord endothelial cells.

The IC ₅₀ of the test compound (the dose of test compound that inhibits 50% of

HU 203 543 Β epithelial cells) was plotted and presented in the following table.

Test compound ic ₅₀ (micrograms / ml) Compound of Formula VI 2.1 x 10 ^-4

The compounds of the invention of the formula I, or pharmaceutically acceptable salts thereof, may be administered orally or parenterally with pharmaceutically acceptable carriers or diluents as vascular inhibitors to mammals, including man, in the form of a capsule, tablet, granule, powder, oral tablet, tongue. tablet and solution form.

Pharmaceutically acceptable carriers which may be used include inorganic or organic materials commonly used in pharmaceutical applications, such as diluents (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), e.g. methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch, etc.), disintegrating agents (e.g., starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch, sodium carboxymethyl starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricants (e.g., magnesium stearate, aerosol, talc, sodium lauryl sulfate, etc.), flavoring agents (e.g., citric acid, citric acid, orange powders, etc.), preservatives (e.g. sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), stabilizers (e.g. citric acid, sodium citrate, acetic acid, etc.), suspending agents (e.g. methylcellulose, polyvinylpyrrolidone aluminum stearate, etc.), dispersants (e.g. surfactants, etc.), aqueous diluents (e.g. water), oils (e.g. sesame oil, etc.), base wax (e.g., cocoa butter, polyethylene glycol, white petrolatum, etc.).

The dosage of the compounds of the formula I according to the invention may vary depending on various factors and, for example, will depend on the type of disease being treated, the weight and / or age of the patient and the route of administration.

A preferred dosage of the compounds of the invention of the formula I is 0.01-10 mg / kg / day for injection and 0.550 mg / kg / day for oral administration.

The following examples illustrate the invention.

Example 1 (1) 9.2 g of 6-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -1-oxaspiro [2,5] octane in 92 ml of dichloromethane (13.1 g) of 4-nitrophenyl chloroformate was added dropwise at room temperature. The mixture was stirred for 3 hours and 5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -6 - [(4-nitrophenoxy) carbonyloxy] -1-oxaspiro was added to the reaction mixture. [2.5] octane is obtained. To the mixture was added morpholine (28.4 g) in one portion. The solution was stirred for 8 hours at room temperature and then diluted with 300 ml of diethyl ether. The solution was washed with saturated NaCl, IN aqueous hydrochloric acid, IN aqueous sodium hydroxide, and saturated NaCl brine. butenyl) oxiranyl] -6- (morpholino-carbonyloxy) -l-oxaspiro [2,5] octane (13.1 g) as an oil; IR (CHC1 _3): 1690,1430,1205 ^cm-1

NMR (CDCl ₃ , delta): 1.05-1.17 (1H, m), 1.20 (3H, s),

1.57 (3H, s), 1.73 (3H, s), 1.79-2.46 (6H, m),

2.54 (1H, d, J = 4Hz), 2.60 (1H, t, J = 6Hz), 3.00 (1H, d, J-4Hz), 3.47 (3H, s) , 3.36-3.58 and 3.58-3.75 (9H, m), 5.22 (1H, m), 5.58 (1H, m).

(2) 1.23 g of 5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -6- (morpholinocarbonyloxy) -1-oxaspiro [2,5] octane A solution of 12 ml of ethyl acetate in hydrogen (0.1 MPa) in the presence of 120 mg of platinum oxide catalyst was hydrogenated for 1 hour. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using diethyl ether-hexane (1: 1 v / v) as eluant and 996 mg of oily 5-methoxy-4- [2-methyl-3- (3-methylbutn) oxiranyl] -6- (morpholino). -carbonyloxy) -1-oxaspiro [2,5] octane. The product crystallizes on standing, m.p. 64-65 ° C.

IR (Nujol): 1700, 1240, 1115 cm ^-1

NMR (CDCl ₃ , delta): 0.90 (6H, d, J = 6Hz), 1.18 (3H, s), 1.08-1.70 (6H, m), 1.80-2. 12 (4H, m), 2.55, (1H, dd, J = 7Hz and 5Hz), 2.60 (1H, d, J = 4Hz), 1 * 2.88 (1H, d, J = 4Hz), 3.36-3.55 (8H, m), 3,603.77 (4H, m), 5.58 (1H, m).

(3) 78 mg of 5-methoxy-4- [2-methyl-3- (3-methylbutyl) oxiranyl] -6- (morpholinocarbonyloxy) -1-oxaspiro [2,5] octane, 125 mg of 3- A mixture of aminothiophenol and 276 mg of potassium carbonate in anhydrous (2 mL) dimethylformamide was stirred for 2 hours at room temperature. The mixture was filtered and the filtrate was diluted with 6 mL of diethyl ether. The solution was washed with water, dried and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with diethyl ether, 88.4 mg of a white powder of 2- [2- {1 - [(3-aminophenylthio) methyl] -1-hydroxy 3-methoxy-4 - [(morpholine-carbonyloxy) -cyclohexyl]} - 2-methyl-3- (3-methylbutyl)] - oxirántkapunk

49-50 ° C

IR (CDCl ₃ ): 3400.1690, 1430, 1240, 1210, 1110 cm ^-1 NMR (CDCl ₃ , delta): 0.91 (6H, d, J = 6Hz), 1.18-1.96 (1 1H, m), 1.43 (3H, s), 2.38 (1H, d, J = 11Hz), 2.46 (1H, t, J = 5Hz), 3.22 (1H, d, J = 13Hz),

3.30 (1H, dd, J = 11 and 2Hz), 3.35 (3H, s), 3.44 (1H, d, J = 13Hz), 3.40-3.60 (4H, m ), 3.60-3.76 (4H, m), 4.18 (1H, s), 5.42 (1H, m), 6.48 (1H, d, J = 6Hz), 6 , 65-6.75 (2H, m), 7.05 (1H, t, J = 6Hz).

(4) 24.1 mg of 2- [2- {1 - [(3-aminophenylthio)] methyl) -1-hydroxy-3-methoxy-4- [morpholinocarbonyloxy] cyclohexyl]} -2-methyl -3- (3-methylbutyl)] oxirane and 18.6 mg of tri3

To a mixture of ethylamine in methylene chloride (1 ml) was added methanesulfonyl chloride (10.5 mg). After stirring for 15 minutes at room temperature, the solution was washed with water, IN hydrochloric acid and brine. The solution was dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using diethyl ether as eluant to give 11.8 mg of 2- (2- [1-hydroxy-1 - {[3- (methanesulfonylamino) phenylthio) -3-methoxy-4 - [(morpholino-). carbonyl oxy) cyclohexyl]} -2-methyl-3 - [(3-methylbutyl)] oxirane crystalline.

M.p. 78-79'C

IR (Nujol): 3400, 1690, 1580, 1240, 1160 cm ^-1 NMR (CDCl ₃ , delta): 0.92 (6H, d, J = 6Hz), 1.21-1.75 (9H, m) ), 1.42 (3H, s), 2.25 (1H, d, J = 10Hz), 3.00 (1H, t, J -5Hz), 3.31-3.45 (10H, m) , 3.533.57 (4H, m), 3.60-3.75 (4H, m), 4.02 (1H, s), 5.42 (1H, m), 7.12-7.46 ( 4H, m).

Example 2

The following compounds were prepared according to the procedure of Example 1 (3).

(1) 2- (2- (1-Hydroxy-3-methoxy-4- (morpholinocarbonyl) -1-dimethylmethyl) -cyclohexyl) -2-methyl-3- (3-methyl-butyl) -oxirane . Oily substance.

IRffilm): 3405,1695,1420,1230,1105 cm ^-1 NMR (CDQ _3, delta): 0.92 (6H, d, J = 6Hz), 1.20-2.00 (9H, m), 1 , 42 (3H, s), 2.38 (1H, d, J = 10Hz), 2.98 (1H, t, J = 5Hz), 3.22 (1H, d, J = 12Hz), 3, 36 (3H, s), 3.45 (1H, d, J = 12Hz), 3.42-3.62

- (5H, m), 3.62-3.75 (4H, m), 4.16 (1H, ss), 5.52 _{; f} (1H, m), 7.13-7.39 (5H, m).

_; (2) 2- (2- (1-hydroxy-3-methoxy-1- (4-methoxyphenylthio) methyl) -4- (morpholinocarbonyloxy) cyclohexyl)) - 2-methyl-3- (3 -methylbutyl) oxirane, oily substance. IR (film): 3405,1690,1585,1490,1240,1110 ^cm-1 NMR (CDQ _3, delta): 0.91 (6H, d, J = 6Hz), 1.22 to 1.96 (9Η, m), 1.44 (3H, s), 2.33 (1H, d, J = 10Hz), 2.96 (1H, t, J = 5Hz), 3.24 (1H, d, J = 12Hz) )

3.30 (1H, dd, J-11 and 2 Hz), 3.36 (3H, s), 3.40 (1H, d, J-12Hz), 3.45-3.62 (4H, m) , 3.62-3.74 (4H, m), 3.28 (3H, s), 4.10 (1H, s), 5.41 (1H, m), 6.82 (2H, d, J = 9 Hz), 7.34 (2H, d, J = 9 Hz).

(3) 2- (2- (1-Hydroxy-3-methoxy-3- (morpholinocarbonyloxy) -1- (phenylthiomethyl) cyclohexyl)) - 2-methyl-3- (3-methyl-2-butenyl) oxirane.

120-121 ° C

IR (Nujol): 3470, 1690, 1240, 1110 cm ^-1 NMR (CDCl ₃ , delta): 1.45 (3H, s), 1.66 (3H, s), 1.73 (3H, s), 1.45-2.00 (4H, m), 2.05-2.28 (1H, m), 2.30-2.55 (2H, m), 2.98 (1H, t, J-6) Hz), 3.25 (1H, d, J-13Hz), 3.32 (1H, d, J-13Hz), 3.34 (3H, s), 3.47-3.80 (9H, m), 4.12 (1H, ss), 5.18 (1H, s, J-7Hz), 5.40 (1H, ss), 7.12-7.40 (5H, m).

Example 3 mg of 6-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -1-oxaspiro [2,5] octane and 3.5 mg of pyridine hydrochloride. , In 5 ml of pyridine

Stir at 70 ° C for 2.35 hours. The mixture was diluted with diethyl ether and washed with brine. The solution was dried and the solvent evaporated in vacuo. The crude oily material was purified by column chromatography on silica gel using diethyl ether / hexane (2: 1) as eluant to give 2- (2- (1- (chloromethyl) -1,4-dihydrox -3-methoxycyclohexyl) -2-methyl-3- (3-methyl-2-butenyl) oxirane is obtained.

IR (CDCl ₃ ): 3.410 cm ^-1

NMR (CDCl ₃ , delta): 1.28-1.42 (1H, m), 1.50 (3H, s), 1.68 (3H, s), 1.77 (3H, s), 1. 65-2.57 (7H, m), 3.00 (1H, t, J-6Hz), 3.23-3.36 (1H, m), 3.36 (3H, s), 3.52 (1H, d, J-11Hz), 3.81 (1H, d, J-11Hz), 3.75-4.02 (1H, s s), 4.24 (1H, m),

5.20 (1H, t, J-8 Hz).

Example 4 (1) 9.2 g of 6-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -1-oxaspiro [2,5] octane and 10.3 g of pyridine To a mixture of dichloromethane (92 mL) was added dropwise 4-nitrophenyl chloroformate (13.1 g) at room temperature. The reaction mixture was stirred for 3 hours at which time

5-Methoxy-4- (2-methyl-3- (3-methyl-2-butenyl) -oxiranyl) -6 - ((4-nitrophenoxy) -carbonyloxy) -1-oxaspiro [2,5] octane produced. To the reaction mixture was added morpholine (28.4 g) in one portion. The solution was stirred for 8 hours at room temperature and then diluted with 300 ml of diethyl ether. The solution was washed with saturated NaCl brine, In aqueous hydrochloric acid, In aqueous sodium hydroxide and finally with saturated NaQ brine. The solution was dried and the solvent evaporated in vacuo. 13.1 g of oily 5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -6- (morpholinocarbonyloxy) -1-oxaspiro [2,5] octane we get.

IR (CH ₃ ): 1690, 1430, 11205 cm ^-1

NMR (CDCl ₃ , delta): 1.05-1.17 (1H, m), 1.20 (3H, s),

1.57 (3H, s), 1.73 (3H, s), 1.79-2.46 (6H, m),

2.54 (1H, d, J = 4Hz), 2.60 (1H, t, J -6Hz), 3.00 (1H, d, J-4Hz), 3.47 (3H, s) , 3.36-3.58 and 3.58-3.75 (9H, m), 5.22 (1H, m), 5.58 (1H, m).

(2) 13.1 g of 5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -6- (morpholinocarbonyloxy) -1-oxaspiro [2,5] octane and 5.7 g of pyridine hydrochloride in 100 ml of pyridine are heated at 70 ° C for 2 hours. The mixture was diluted with diethyl ether. The solution was washed with aqueous hydrochloric acid 1N and brine, dried and concentrated in vacuo. The crude oily material (15.0 g) was purified by column chromatography over silica gel using diethyl ether / hexane (1: 2 v / v) as eluent. White powder, 13.4 g of 2- (2- (1- (chloromethyl) 1-hydroxy-3-methoxy-4- (morpholinocarbonyloxy) cyclohexyl)) - 2-methyl-3- (3-methyl) -2-butenyl) oxirane is obtained. The powder was recrystallized from ethanol / water (1: 1.15 v / v) to give 5.7 g of colorless crystals.

92-93'C

IR (Nujol): 3480,1680,1240 ^cm-1

NMR (CDCl ₃ , delta): 1.34 (1H, dr, J-15.4 Hz), 1.50 (3H, s), 1.67 (3H, s), 1.74 <3H, s) , 1.72-1.92 (2H, m), 1.95-2.28 (2H, m), 2.34-2.57 (2H, m),

HU 203 543 Β

2.98 (1H, t, J = 8Hz), 3.26 (1H, dd, J = 14.4Hz),

3.33 (3H, s), 3.42 (1H, d, J = 14Hz), 3.42-3.57 (4H, m), 3.60-3.78 (4H, m), 3 , 89 (1H, d, J-14Hz), 4.16-4.30 (1H, ds), 5.20 (1H, ds,

J = 8Hz), 5.38-5.46 (1H, m). 5

Example 5 (1) 423 mg of 6-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -1-oxaspiro [2,5] octane and 474 mg of pyridine. To a mixture of 10 ml of dichloromethane was added dropwise at room temperature 1.2 g of (4-nitrophenyl) chloroformate. The mixture was stirred for 3 hours and

5-methoxy-4- (2-methyl-3- (3-methyl-2-butenyl) oxiranyl) 6 - ((4-nitrophenoxy) carbonyloxy) -1-oxaspiro [2,5] octane is formed 2.25 g of 3-amino-1-propane are added in one portion. The mixture was stirred at room temperature for 2 hours and then diluted with diethyl ether (20 mL). 400 mg of crystalline 6 ((3-hydroxypropyl) carbamoyloxy) -5-methoxy-4- (2-methyl-3- (3-methyl-2-butenyl) oxiranyl) -1-oxaspiro [2, 5] octane is obtained

M.p. 57-58 ° C

IR (Nujol): 3350, 1680, 1530, 1260 cm ^-1

NMR (CDCl ₃ , delta): 1.00-1.13 (1H, m), 1.21 (3H, s),

1.65 (3H, s), 1.73 (3H, s), 1.65-2.50 (10, m), 2.52-2.61 (2H, m), 2.98 (1H) , d, J-4Hz), 3,203.45 (1H, m), 3.48 (3H, s), 3.58-3.75 (4H, m),

5.20 (1H, s, J = 8 Hz), 5.50 (1H, s, s).

(2) 15 mg (6 - ((3-hydroxypropyl) carbamoyloxy) -5-methoxy-4- (2-methyl-3- (3-methyl-2-butenyl) oxiranyl) -1- 35 oxaspiro [2 , 5] octane and 12.3 mg of pyridine in 1 ml of dichloromethane, 32 mg of (4-nitrophenyl) chloroformate are added dropwise at room temperature, and the mixture is stirred for 2 hours and 5-methoxy-4- [2-methyl-3 ( 3-Methyl-2-butenyl) oxiranyl] -6 - [(37 (4-nitrophenoxy) 40-carbonyloxypropyl) carbamoyloxy] -1-oxaspiro [2,5] octane 7 mg of methylamine is formed. A 30% methanolic solution was added in one portion, the mixture was stirred at room temperature for 1 hour, and then diluted with diethyl ether (5 mL). The solution was washed with saturated NaCl brine, then with IN hydrochloric acid, IN aqueous sodium hydroxide and finally with NaCl. The crude oily material was purified by column chromatography on silica gel using diethyl ether and 13.8 g of crystalline 5-methoxy-4- [2-meth m.p. 3 - (3-Methyl-2-butenyl) -oxiranyl] -6 - ((3-methylcarbamoyloxy) -propyl] -carbamoyloxy) -1-oxaspiro [2,5] octane is obtained.

52-54 ° C 55

IR (Nujol): 3350, 1700, 1525, 1460, 1110 cm ^-1 NMR (CDCl ₃ , delta): 1.00-1.12 ( ¹ H, m), 1.71 (3 H, s),

1.78 (3H, s), 1.80 (3H, s), 1.81-2.48 (9H, m),

2.50-2.62c (2H, m), 2.97 (3H, d, J = 4Hz), 2.98 (1H, d, J-4Hz), 3.10-3.38 (2H) , m), 3.45 (3H, 60

s), 3.64 (1 H, dd, J 3 Hz and 11 Hz), 4.02-4.38 (2 H, m), 4.93-5.13 (1 H, m), 5.13- 5.25 (1H, m)

5.50 (lH, bs).

(3) The following compound was prepared according to the procedure of Example 3.

2- [2- / l- (chloromethyl) -l-hydroxy-3-methoxy-4- (3- / methylcarbamoylbxy / carbamoyloxy-propyl) -cyclohexyl /] 2-methyl-3- (3- methyl-2-butenyl) oxirane. Oily substance.

IR (CHCl ₃ ): 3450.1705 cm ^-1

NMR (CDCl ₃ , delta): 1.29-1.44 (1 H, m), 1.49 (3 H, s),

1.66 (3H, s), 1.74 (3H, s), 1.77-2.27 (6H, m),

2.31-2.56 (2H, m), 2.79 (3H, d, J = 7Hz), 2.97 (1H, s, J-8Hz), 3.20-3.36 (3H) , m), 3.32 (3H, s), 3.49 (1H, d, J-13Hz), 3.86 (1H, d,

J-13 Hz), 4.17 (3H, s s, J-8 Hz) 4.65-4.80 (1H, s s), 4.92-5.06 (1H, s s), 5, 18 (HH, dd,

J -9 Hz), 5.31-5.40 (1H, s s).

Example 6 (1) The following compound was prepared according to the procedure of Example 4 (1).

6- (methylcarbamoyloxy) -5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] oxaspiro [2,5] octane, * (11 mg), crystalline.

92-93 ° C <5

IR (CHC1 _3): 3460,3360,1715 ^cm-1 <

NMR (CDCl ₃ , delta): 1.0-1.15 (1H, m), 1.20 (3H, s), 1.66 (3H, s), 1.73 (3H, s), 1.65 -2.54 (6 H, m),,

2.54 (1H, d, J = 5Hz), 2.55 (1H, t, J = 6Hz), 2.7 (3H, d, J = 5Hz), 2.97 (1H, d, J = 5Hz), 3.47 (3H, s), 3.64 (1H, dd, J = 11Hz and 3Hz), 4.75 (1H, s')

s), 5.20 (lH, t, J = 8Hz), 5.50 (lH, bs). >

(2) The following compound is prepared by the procedure of Example 4 (2).

2- (271- (Chloromethyl) -1-hydroxy-3-methoxy-4- (methylcarbamoyloxy) -cyclohexyl) -2-methyl-373-methyl-2-butenyl-oxirane.

IR (CHC1 _3): 3460,1705,1505 ^cm-1

NMR (CDCl ₃ , delta): 1.29-1.42 (1 H, m), 1.50 (3 H, s),

1.66 (3H, s), 1.73 (3H, s), 1.78-2.26 (4H, m),

2.33-2.57 (2H, m), 2.82 (3H, d, J = 8Hz), 2.97 (1H, t, J = 9Hz), 3.26 (1H, dd, J) -14.3Hz), 3.33 (3H, s), 3.46 (1H, d, J-14Hz), 3.85 (1H, d,

J -16Hz), 4.05-4.30 (1H, ss), 4.66-4.80 (1H, ss), 5.20 (1H, ss, J-8Hz), 5 , 33-5.41 (1H, sz s).

Example 7 (1) The following compound was prepared according to the procedure of Example 4 (1).

6- (2-ethylcarbamoyloxy) -5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -1-oxaspiro [2,5] octane.

Op.:65°C

IR (CHCl ₃ ): 3450.1705 cm ^-1

NMR (CDCl ₃ , delta): 0.99-1.30 (1H, m), 1.14 (3H, t,

J-8 Hz), 1.22 (3H, s), 1.67 (3H, s), 1.75 (3H, s),

1.78-2.48 (6H, m), 2.56 (1H, d, J-4Hz), 2.58 (1H, t, J-5Hz), 2.99 (1H, d, J) -4 Hz), 3.22 (2H, m), 3.45 (3H, s), 3.64 (1H, dd, J-2 and -1 Hz),

HU 203 543 Β

4.75 (1H, ss), 5.21 (1H, t, J = 7Hz), 5.50 (1H, ss).

(2) The following compound was prepared according to the procedure of Example 4 (2).

2- (2- (l- (chloromethyl) -4- (ethyl-carbamoyloxy) -l-hydroxy-3-methoxy-cyclohexyl)) - 2-methyl-3- (3-methyl-2-butenyl) - oxirane. Oily substance.

IR (CHCl ₃ ): 3500, 1720, 1135 cm ^-1

NMR (CDCl ₃ ): 1.17 (3H, t, J-6Hz), 1.30-1.44 (1H, m), 1.50 (3H, s), 1.65 (3H, s) , 1.73 (3H, s), 1.782.56 (6H, m), 2.97 (1H, t, J = 6Hz), 3.23 (2H, m), 3.33 (3H, s) , 3.25-3.35 (1H, m), 3.48 (1H, d, J = 11Hz), 3.86 (1H, d, J = 11Hz), 4.16 (1H, s) ), 4.75 (1H, ss), 5.20 (1H, t, J-7Hz), 5.34 (1H, ss).

Example 8 (1) The following compound was prepared according to the procedure of Example 4 (1).

5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl)] - 6- (morpholino-carbamoyloxy) -l-oxaspiro [2,5] octane.

122-123 ° C

IR (Nujol): 3250, 1700, 1525, 1250, 1150, 1100 cm ^-1 NMR (CDCl ₃ , delta): 1.04-1.16 (1H, m), 1.22 (3H, s),

1.65 (3H, s), 1.75 (3H, s), 1.78-2.48 (6H, m),

2.55 (1H, d, J = 4Hz), 2.56 (1H, t, J = 6Hz), 2.76-2.93 (4H, s t, J = 5Hz), 3.64 ( 1H, dd, J = 12 and = 2 Hz), 3.45 (3H, s), 3.73-3.86 (4H, s t, J = 5 Hz), 5.20 (1H, s t, J = 7Hz), 5.52 (1H, ss), 5.74 (1H, ss).

(2) The following compound was prepared according to the procedure of Example 4 (2).

2r [(2- [l- (chloromethyl) -l-hydroxy-3-methoxy-4- (morpholino-carbamoyloxy) cyclohexyl]} - 2-methyl-3- (3-methyl-2-butenyl) - oxirane.

49-50 ° C

IR (Nujol): 3480.1685 cm ^-1

NMR (CDCl ₃ , delta): 1.27-1.42 (1H, m), 1.48 (3H, s),

1.66 (3H, s), 1.75 (3H, s), 1.70-2.58 (6H, m), 2.86 (4H, st, J = 5Hz), 2.96 (1H, st, J = 7Hz), 3.27 (1H, dd, J-12 and 2Hz), 3.32 (3H, s), 3.46 (1H, d, J = 11Hz), 3.81 (4H) , s t, J = 5Hz, 3.88 (1H, d, J-11Hz), 4.02-4.26 (1H, s s), 5.18 (1H, s, J = 8) Hz), 5.34-5.44 (1H, ss), 5.615.80 (1H, ss).

Claims (7)

PATENT CLAIMS A process for the preparation of the cydohexane derivatives of the formula I and their salts, wherein R ¹ is a methyl substituted by a halogen atom or a phenyl optionally substituted on the phenyl by an amino group, a C 1-4 alkoxy group or a C 1-4 alkanesulfonylamino group. thiomethyl group; R ² is C 1-4 alkoxy; R ³ is a group of formula (TV) or a group of formula (V), and R ⁴ is hydrogen, C 1 -C 4 alkylcarbamoyl, C 1 -C 4 alkylcarbamoyloxy (C 1 -C 5) alkylcarbamoyl, morpholinocarbonyl or morpholino; carbamoyl, characterized in that a) a compound of formula (Π) wherein R ² , R ³ and R ⁴ are as defined above, with a compound of formula (ΠΙ) or a salt thereof, wherein: X is a halogen atom, or a phenyl-thio group optionally substituted on the phenyl group with an amino group, a C 1-4 alkoxy group or a C 1-4 alkanesulfonylamino group, or b) for the preparation of compounds of formula Ic wherein R ² , R ³ and R ⁴ are as defined above and R ⁵ is a sulfonylamino group of C 1 -C 4 alkane 3, a compound of formula Ib or a salt thereof wherein R ² , R ³ and R ⁴ are as defined above, with an acylating agent having a C 1-4 alkanesulfonyl group as defined above, And optionally converting the resulting free compound into a salt thereof. (Priority: 11.08.1989) A process according to claim 1 for the preparation of a compound of formula I wherein: 3 R ¹ is a halogen substituted methyl; R ² is 1- C4 alkoxy; R ³ is a group of formula IV and R ⁴ is hydrogen, Characterized in that the appropriate starting materials are used. (Priority: 12/8/1988) A process according to claim 1 for the preparation of a compound of formula I wherein: R ^{1 is} a halogen-substituted methyl; 3 R ^{2 is C} 1-4 alkoxy; R ^{3 is} (TV) and R ^{4 is} as defined in claim 1, characterized in that it is based on appropriately substituted materials. (Priority: 10/4/1989) A process for the preparation of a compound of formula (I) according to claim 1 wherein R ^{1 is} optionally substituted on the phenyl with an amino group, Phenylthiomethyl substituted with C 1-4 alkoxy or C 1-4 alkanesulfonylamino, and R ² , R ³ and R ^{4 are} as defined in claim 1, characterized in that they are substituted with suitable substituents . (Priority: April 28, 1989) Process (a) according to claim 1 for the preparation of compounds of general formula (I), wherein R ^{1 is} a halogen-substituted methyl; R ^{2 is C} 1-4 alkoxy; R ^{3 is} (TV) and R ^{4 is} morpholinocarbonyl, EN 203 543 Β characterized in that it is based on appropriately substituted materials. (Priority: 10/4/1989) A process for the preparation of a compound of formula (I) according to claim 1 wherein: R ¹ is chloromethyl; R ² is methoxy; R ³ is a group of formula (TV) and R ⁴ is morphinocarbonyl, characterized in that the appropriate starting materials are used. (Priority: 10/4/1989) 7. A process for the preparation of a pharmaceutical formulation comprising the active ingredient and / or a pharmaceutically acceptable salt of one or more cyclohexane derivatives of the formula I according to claim 1, wherein R ¹ , R ² , R ³ and R ^{4 are} processed into pharmaceutically acceptable forms with the pharmaceutically acceptable carriers as defined in claim 1. (Priority: 11.08.1989)